Coinfection with hepatitis C (HCV) is common in individuals with the human immunodeficiency virus (HIV) because of shared risk factors and modes of transmission. Following the introduction of combination antiretroviral therapy, HCV infection has emerged as one of the most important causes of morbidity and mortality in HIV-infected individuals. Complications of liver disease are now leading reasons for hospital admission among HIV infected patients. Liver disease appears to be accelerated in HIV/HCV coinfected persons. However the severity of hepatic disease is highly variable, even in persons who share HCV viral characteristics, duration of infection, age and gender. The factors responsible for variability in disease course have not been fully elucidated. Most studies of HIV/HCV patients show that coinfection leads to more progressive liver disease than HCV alone but men predominate in these studies and information on women is needed since sex differences are recognized in HCV and other viral liver diseases. Women and children infected with HCV alone clear the virus at a higher rate than men, and develop liver disease at a slower rate and with fewer cases of cirrhosis. The rate of progression of liver fibrosis in women who are coinfected with HIV and HCV is not known. Progression in dually infected women may be more rapid than among those with HCV mono-infection and yet be slower than in men coinfected with HIV/HCV. The advantages of female sex, if they exist, may be lost at menopause, when production of ovarian sex steroids ceases. This study will address the critical issue of fibrosis progression in HIV/HCV coinfection among women, and the impact of menopause on this progression. We hypothesize that women with HIV and HCV will have variable fibrosis progression of liver disease related to HIV status. We further hypothesize that the rate of fibrosis will increase, coincident with completion of the menopausal transition, indicating that any sex advantage in hepatic disease will disappear in older women. This grant will utilize the established research infrastructure for longitudinal follow-up of subjects in WIHS and the availability of results from clinical data, HIV and HCV data as well as from stored biologic specimens, will serve as a platform for cutting-edge collaborative studies. The WIHS is a unique resource for addressing these aims. PUBLIC HEALTH RELEVANCE: This proposal will study the progression of liver disease in women with HIV and hepatitis C coinfection to determine the host and viral cofactors which predict progression of disease. There is great variation in the severity of disease, even in subjects with similar HCV viral characteristics, length of infection, age and gender. The causes of this variation are not fully elucidated. Most studies of patients coinfected with HIV and HCV show that coinfection leads to more progressive liver disease than HCV alone but men predominate in these cohorts. Women and children infected with HCV alone clear the virus at a higher rate than men, develop less progression of liver disease culminating in fewer cases of cirrhosis than men but the rate of progression of liver fibrosis in women co-infected with HIV and HCV is not known. We will determine the role of menopause and HIV in progression of liver disease in HIV/HCV co-infected women. This will have important consequences as women with mild or no liver fibrosis are not recommended for current therapy while those with significant fibrosis should be treated with pegylated interferon and ribavirin, the standard of care for HCV and HIV infected patients.